Tumor promoting phorbol esters have been reported to stimulate cellular proliferation in vitro as well as in vivo, but whether this stimulation is due to changes in membrane permeability, membrane receptor sites, or cellular configuration is not clear. Among the earliest changes induced by the potent tumor promoter, 12-o-tetradecanoyl phorbol acetate (TPA) are in membrane transport where, for example, TPA (10 to the minus 8th power-10 to the minus 6th power M) stimulates the uptake by 3T3 mouse embryonic fibroblasts of the K ion marker 86 Rb ion by 1.5-2.0 fold and the enhancement of 32 Pi incorporation within a few minutes of administration. Both influxes are ouabain-sensitive in accord with the idea that an early effect of TPA is to influence Na ion - K ion movements. These effects are also accompanied by an increase in glycolysis and lactate efflux which may be secondary to activation of membrane (Na ion plus K ion) -ATPase. Since prostaglandin F2 alpha exhibits similar activity, it is proposed that such responses be examined further to determine whether phorbol esters and prostaglandins act directly at common membrane sites or whether the response is due to an indirect linkage. Since the cell response has been observed to be dependent on cell cycle activity, it appears necessary to study correlations of responses under different conditions and with different cell types. One cell type of particular interest is the C3H-10T1/2 fibroblasts in which evidence of a correlate of in vivo tumor promotion has been demonstrated. Further, it is proposed that it be determined whether early receptor-mediated drug responses (e.g. prostaglandins, catecholamines) observed in vitro can be correlated with tumor promotion in vivo. An attempt will be made to obtain evidence for a model in which the proliferative response may not be the most important aspect of tumor promotion but that consideration of cell cycle activation and multiple restriction points is necessary. It appears necessary to define those early in vitro responses which are related to, and possibly dependent upon the position of the cell within the cell cycle, those which reflect general cell injury, and those which are closely related to the activity of tumor promotion in vivo.